U.S. application Ser. No. 146,714 filed Nov. 10, 1993 ((file HA619b) (incorporated herein by reference) now abandoned, discloses thrombin inhibitors of the structure ##STR2## including all stereoisomers, wherein n is 0, 1 or 2; G is an amido moiety which includes a cyclic member;
R is hydrogen, hydroxyalkyl, aminoalkyl, alkyl, cycloalkyl, arylalkyl, alkenyl, alkynyl, amidoalkyl, arylalkoxyalkyl or an amino acid side chain, either protected or unprotected; PA1 R.sup.1 and R.sup.2 are independently hydrogen, lower alkyl, cycloalkyl, aryl, hydroxy, alkoxy, keto, thioketal, thioalkyl, thioaryl, amino or alkylamino; or R.sup.1 and R.sup.2 together with the carbons to which they are attached form a cycloalkyl, aryl or heteroaryl ring; PA1 R.sup.3 is alkyl, arylalkyl, aryl, heteroaryl, quinolinyl or tetrahydroquinolinyl; PA1 including pharmaceutically acceptable salts thereof, and PA1 G is ##STR3## wherein p is 0, 1 or 2; Q is a single bond or ##STR4## A is aryl or cycloalkyl or an azacycloalkyl ring of 4 to 8 members or an azaheterocycloalkyl ring of 6 to 8 members of the structure ##STR5## where X is CH.sub.2, O, S or NH; q is 0, 1, 2, 3 or 4, provided that PA1 q is 0, 1, 2, 3 or 4 if X is CH.sub.2 ; PA1 q is 2, 3 or 4 if X is O, S or NH; PA1 y.sup.1 and y.sup.2 are independently H, lower alkyl, halo or keto; PA1 R.sup.4 is guanidino, amidino or aminomethyl; with the provisos that where A is aryl or cycloalkyl, R.sup.4 is guanidino, amidino or aminomethyl, PA1 Q is a single bond or ##STR7## Y.sup.1 and Y.sup.2 are independently H, lower alkyl or halo; X is CH.sub.2, --CH.dbd.CH--, O, S or NH; PA1 q is 0, 1, 2, 3 or 4 if X is CH.sub.2 or --CH.dbd.CH--; PA1 q is 2, 3 or 4 if X is O, S or NH; PA1 and P.G. is an amine protecting group which preferably is benzyloxycarbonyl (CBZ) or t-butoxycarbonyl (BOC), and the N-, X-containing ring is referred to as azacycloalkyl, azacycloalkenyl, azaheterocycloalkyl or the A ring, which process includes the steps of providing a protected guanylpyrazole of the structure ##STR8## where P.G. is as defined above, and reacting the protected guanylpyrazole II with a compound of the structure ##STR9## where p, Q, x, q and Y.sup.1 and Y.sup.2 are as defined above and Rpg is an N-protecting group, for example, a Schiff base such as .dbd.CHC.sub.6 H.sub.5, CBZ, or BOC in the presence of a basic catalyst, such as triethyl-amine, or diisopropylethylamine, and preferably 1, 8-diazabicyclo-[5.4.0]undec-7-ene (DBU) or 1, 5-diazabicyclo-[4.3.0]non-5-ene (DBN), to form the guanidine intermediate I. PA1 R.sup.1 and R.sup.2 are independently hydrogen, lower alkyl, cycloalkyl, aryl, hydroxy, alkoxy, oxo (also referred to as keto), thioxo, thioketal, thioalkyl, thioaryl, amino or alkylamino; or R.sup.1 and R.sup.2 together with the carbons to which they are attached form a cycloalkyl, aryl, or heteroaryl ring; and PA1 R.sup.3 is lower alkyl, aryl, arylalkyl, heteroaryl, quinolinyl or tetrahydroquinolinyl; PA1 n is 0, 1 or 2; PA1 and p, Q, X, q, Y.sup.1 and Y.sup.2 are as defined hereinbefore.; PA1 provided that where x is a hetero atom (that is, A ring is azaheterocycloalkyl), then there must be at least a 2-carbon chain between x and any N atom in the ring outside the ring A; PA1 which process includes the steps of providing the substituted piperidinoguanidine intermediate I, reacting the guanidine intermediate I with an acid of the structure V ##STR12## in a carbodiimide coupling reaction, in the presence of a coupling agent such as ethyl 3-(3-dimethylamino)propyl carbodiimide hydrochloride (WSC) or dicyclohexyl-carbodiimide (DCC) or diisopropyl-carbodiimide (DIC), and 1-hydroxybenzotriazole monohydrate (HOBT), and optionally in the presence of a suitable base such as N-methylmorpholine (NMM) or triethylamine, and in the presence of a solvent such as aqueous isopropanol, dimethylformamide (DMF), THF, dichloromethane, or N-methylpyrrolidone, to form the protected compound VI ##STR13## and removing the protecting group, by standard deprotection procedures, for example, by hydrogenation where P.G. is CBZ, or by treatment with trifluoroacetic acid or anhydrous HCl where P.G. is BOC, to form the guanidine thrombin inhibitor Iv. PA1 R is aralkyl or hydroxyalkyl; PA1 R.sup.1 and R.sup.2 are each H; PA1 n is 0or 1.
where A is azacycloalkyl or azaheterocycloalkyl, R.sup.4 is amidino; PA2 where A is azaheterocycloalkyl, then there must be at least a 2-carbon chain between X and any N atom in the ring or outside the ring.